Colorectal cancer residual disease at maximal response to EGFR blockade displays a druggable Paneth cell–like phenotype

• DOI: 10.1126/scitranslmed.aax8313
• Publication Date: 2020-08-05T23:30:12Z
• Authors: Barbara Lupo; Francesco Sassi; Marika Pinnelli; Francesco Galimi; Eugenia R. Zanella; Valentina Vurchio; Giorgia Migliardi; Paolo Armando Gag...; Alberto Puliafito; Daria Manganaro; Paolo Luraghi; Michael Kragh; Mikkel W. Pedersen; Ivan D. Horak; Carla Boccaccio; Enzo Medico; Luca Primo; Daniel Nichol; Inmaculada Spiteri; Timon Heide; Alexandra Vatsiou; Trevor A. Graham; Elena Élez; Guillem Argiles; Paolo Nuciforo; Andrea Sottoriva; Rodrigo Dienstmann; Diego Pasini; Elena Grassi; Claudio Isella; Andrea Bertotti; Livio Trusolino
• Keywords: Druggability; Drug response

Blockade of epidermal growth factor receptor (EGFR) causes tumor regression in some patients with metastatic colorectal cancer (mCRC). However, residual disease reservoirs typically remain even after maximal response to therapy, leading relapse. Using patient-derived xenografts (PDXs), we observed that mCRC cells surviving EGFR inhibition exhibited gene expression patterns similar those a quiescent subpopulation normal intestinal secretory precursors Paneth cell characteristics. Compared untreated tumors, these pseudodifferentiated remnants had reduced genes encoding EGFR-activating ligands, enhanced activity human 2 (HER2) and HER3, persistent signaling along the phosphatidylinositol 3-kinase (PI3K) pathway. Clinically, properties from PDX models were detected lingering tumors responsive individuals who experienced early recurrence. Mechanistically, reprogramming neutralization was mediated by inactivation Yes-associated protein (YAP), master regulator epithelium recovery injury. In preclinical trials, Pan-HER antibodies minimized disease, blunted PI3K signaling, induced long-term control treatment discontinuation. We found tolerance is characterized an intrinsic lineage program drives both regenerative during repair EGFR-dependent tumorigenesis. Thus, our results shed light on CRC plasticity as adaptive escape mechanism EGFR-targeted therapy suggest opportunities preemptively target disease.